In accordance with the present invention, there is now provided a new and improved process for preparing the prodrug herein before discussed above, viz., 7-(1.alpha.,5.alpha.,6.alpha.)-6-(L-Ala-L-Ala-amino)-3-azabicyclo3.1.0!h ex-3-yl-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine -3-carboxylic acid as a pharmaceutically acceptable acid addition salt, in pure form and in high yield by a novel three-step method, starting from the appropriate N-protected drug ester that is typically an N-protected 7-(1.alpha.,5.alpha.,6.alpha.)-6-amino-3-azabicyclo3.1.0!hex-3-yl!-fluor o-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid lower alkyl (C.sub.1 -C.sub.4) ester and proceeding through the following sequence of reactions, as outlined in the accompanying reaction scheme. ##STR1##
More particularly, the overall process of the invention involves the steps of:
(a) treating an N-protected 7-(1.alpha.,5.alpha.,6.alpha.)-6-amino-3-azabicyclo3.1.0!hex-3-yl!-6-flu oro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid C.sub.1 -C.sub.4 alkyl ester see formula (V)!, wherein R' is an N-protecting group like benzyloxycarbonyl, C.sub.1 -C.sub.4 alkoxycarbonyl or C.sub.1 -C.sub.4 alkanoyl and R" is an alkyl group having from one to four carbon atoms, with a strongly-protic acid to selectively remove the N-protecting group;
(b) then condensing the resulting amino ester compound see formula (II)! with an N-protected L-alanyl-L-alanine dipeptide compound having formula (III)! in the presence of dehydrating agent to form the corresponding N-protected prodrug ester as the desired condensation product; and
(c) thereafter hydrolyzing the intermediate N-protected prodrug ester see formula (I)! in the presence of a pharmaceutically-acceptable strong acid to convert said intermediate N-protected prodrug ester to the corresponding naphthyridinone L-Ala-L-Ala prodrug acid final product having formula (IV)!, as indicated above, in the form of a pharmaceutically acceptable acid addition salt.
In this way, for example, a compound such as 7-(1.alpha.,5.alpha.,6.alpha.)-6-(tert.-butoxycarbonylamino)-3-azabicyclo 3.1.0!hex-3-yl!-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naph thyridine-3-carboxylic acid ethyl ester is readily converted, via the intermediates 7-(1.alpha.,5.alpha.,6.alpha.)-6-amino-3-azabicyclo-3.1.0!hex-3-yl!-6-fl uoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxyli c acid ethyl ester and 7-(1.alpha.,5.alpha.,6.alpha.)-6-(N-tert.-butoxycarbonyl-L-Ala-L-Ala-amin o)-3-azabicyclo3.1.0!hex-3-yl!-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro -4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester, to 7-(1.alpha.,5.alpha.,6.alpha.)-6-(L-Ala-L-Ala-amino)-3-azabicyclo3.1.0!h ex-3-yl!-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridin e-3-carboxylic acid as a pharmaceutically acceptable acid addition salt and preferably, as the methanesulfonic acid addition salt. The latter prodrug acid final product is useful as a water-soluble prodrug of 7-(1.alpha.,5.alpha.,6.alpha.)-6-amino-3-azabicyclo-3.1.0!hex-3-yl!-6-fl uoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1-naphthyridine-3-carboxylic acid, which is known to be useful as a therapeutically-effective antibacterial agent.
Accordingly, there is especially included within the purview of this invention a novel condensation method step (b)! for preparing an N-protected prodrug ester compound of the formula: ##STR2## wherein R' is benzyloxycarbonyl, C.sub.1 -C.sub.4 alkoxycarbonyl or C.sub.1 -C.sub.4 alkanoyl and R" is an alkyl group having from one to four carbon atoms, which comprises the step of condensing the corresponding free amino ester compound of the formula ##STR3## wherein R" is as previously defined, with at least an equimolar amount of a nitrogen-protected L-alanyl-L-alanine dipeptide compound of the formula ##STR4## wherein R' is also as previously defined, in the presence of a standard organic dehydrating agent that is suitable for peptide bond formation, with the said condensation reaction being most efficiently conducted in a reaction-inert aprotic organic solvent at a temperature that is desirably in the range of from about 10.degree. C. up to about 40.degree. C., so as to yield the corresponding N-protected prodrug ester of the formula (I) as the desired condensation product of the reaction.
Additionally, the invention also especially includes within its scope a novel method of hydrolysis step (c)! for preparing the corresponding prodrug acid, in the form of a pharmaceutically acceptable acid addition salt, from the corresponding N-protected prodrug ester compound of structural formula (I), obtained in the foregoing condensation reaction step, which further comprises subjecting the aforesaid N-protected prodrug ester compound to acid hydrolysis by contacting said ester with a mixture of water and a pharmaceutically-acceptable strong mineral or organic acid. More particularly, the hydrolysis reaction is most efficiently conducted in the presence of a water-miscible, reaction-inert polar organic as diluent and at a temperature that lies within the range of from about room temperature up to about the reflux temperature of the reaction mixture, so as to effectively cleave both the R' and R" groups from the structure (I) compound and thus afford the desired naphthyridinone antibacterial L-Ala-L-Ala prodrug acid compound having the formula ##STR5## in the form of a pharmaceutically acceptable acid addition salt.
Also especially disclosed within the purview of this invention is a novel nitrogen-deprotecting method step (a)! for preparing the step (c) free amino ester starting compound (i.e., N-deprotected drug ester) of structural formula (II), which involves treating a corresponding N-protected amino ester compound (i.e., N-protected drug ester) of the formula: ##STR6## wherein R' is benzyloxycarbonyl, C.sub.1 -C.sub.4 alkoxycarbonyl or C.sub.1 -C.sub.4 alkanoyl and R" is an alkyl group having from one to four carbon atoms, with an excess in moles of a strongly-protic acid in the presence a reaction-inert aprotic organic solvent at a temperature that is most desirably in the range of from about 15.degree. C. up to about 45.degree. C., to selectively remove the R.sup.1 group and so form the corresponding free amino ester compound of the aforesaid formula (II).